摘要：SummaryNeurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions inC9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used aC9ORF72Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set ofC9ORF72and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.Graphical abstractDisplay OmittedHighlights•Multi-omic analysis of differentiated C9ORF72 iPSC-derived motor neurons•Network-based integrative computational analysis•Pathogenic versus compensatory pathways elucidated using C9ORF72Drosophilamodel•Pathways confirmed with alternative differentiation protocol and postmortem dataBiological sciences; Neuroscience; Systems neuroscience; Systems biology; Omics
